Although caffeine use for apnea of prematurity is well studied, the long-term safety and benefit of routine early caffeine administration has not been explored. Our objective was to determine the association between early (within 2 days of birth) versus late caffeine exposure and neurodevelopmental outcomes in preterm infants.
Infants of <29 weeks’ gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network units and then assessed at Canadian Neonatal Follow-up Network centers were studied. Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months’ corrected age.
Of 2108 neonates who were eligible, 1545 were in the early-caffeine group and 563 were in the late-caffeine group. Rates of bronchopulmonary dysplasia, patent ductus arteriosus, and severe neurologic injury were lower in the early-caffeine group than in the late-caffeine group. Significant neurodevelopmental impairment (adjusted odds ratio 0.68 [95% confidence interval 0.50–0.94]) and odds of Bayley Scales of Infant and Toddler Development, Third Edition cognitive scores of <85 (adjusted odds ratio 0.67 [95% confidence interval 0.47–0.95]) were lower in the early-caffeine group than in the late-caffeine group. Propensity score–based matched-pair analyses revealed lower odds of cerebral palsy and hearing impairment only.
Early caffeine therapy is associated with better neurodevelopmental outcomes compared with late caffeine therapy in preterm infants born at <29 weeks’ gestation.
Comments
RE: Early Caffeine and Neurodevelopmental Outcomes
We thank Dr. Hand and his colleague for commenting about our recent publication. We reported that early caffeine therapy is associated with better neurodevelopmental outcomes compared with late caffeine therapy in preterm infants born at <29 weeks’ gestation.1 Our study1 results did not show a significant difference in the rate of mortality between two groups, a finding that resonates well with other studies.2-7 A systematic review and meta-analysis of early use of caffeine in 59,136 very low birth weight infants, suggested that early caffeine use has beneficial effects on neonatal outcomes including mortality (OR 0.90; 95%CI 0.83-0.94) and bronchopulmonary dysplasia.8 In the absence of a large randomized controlled trial (RCT) study investigating the role of early caffeine and outcomes, we believe that our study results are important. We agree that our data are retrospective which is inherently associated with residual confounding. Multivariable logistic regression, and propensity score matched analysis allow researchers to assess different therapeutic strategies with adjustment for confounders.9 However, residual confounding remains in an observational study in spite of the use of statistical techniques to control for known confounders.
We would also like to indicate that a RCT 10 of early versus delayed caffeine was stopped prematurely due to a trend of higher mortality in the early caffeine group. However, it was not statistically significantly different (p= 0.22) between groups. The results should be interpreted with caution when a trial is stopped prematurely for the outcome which was not their primary outcome. The authors themselves have cautioned against over-interpretation of their results.10 Katheria et al. in a pilot RCT of early caffeine versus routine caffeine therapy in extremely premature infants did not observe any harmful effects or effect on mortality.4 We agree that we need large randomized studies to properly assess efficacy and safety of early caffeine administration.
We agree with Hand and Noble that whether to administer caffeine early or not should be made after judicious consideration by attending team. However, it is also true that the existing evidence available to the team to make decision stems mainly from observational studies and our study contributes to this body of evidence from a perspective of a large, multicenter, national cohort with neurodevelopmental data.
Abhay Lodha, MD, DM, MSc
Associate Professor, Department of Pediatrics & Community Health Sciences,
Univeristy of Calgary, Calgary, Canada
Prakesh S Shah, MD, MSc
Professor, Department of Pediatrics,
Mount Sinai Hospital, Toronto,
University of Toronto, Canada
References
1. Lodha A, Entz R, Synnes A, Creighton D, Yusuf K, Lapointe A, et al. Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants. Pediatrics. 2019;143(1).
2. Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, et al. Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. J Pediatr. 2010;156(3):382-387.
3. Gupte AS, Gupta D, Ravichandran S, Michelle Ma M, Chouthai NS. Effect of early caffeine on neurodevelopmental outcome of very low-birth weight newborns. J Matern Fetal Neonatal Med. 2016;29(8):1233-1237.
4. Katheria AC, Sauberan JB, Akotia D, Rich W, Durham J, Finer NN. A Pilot Randomized Controlled Trial of Early versus Routine Caffeine in Extremely Premature Infants. Am J Perinatol. 2015;32(9):879-886.
5. Kua KP, Lee SW. Systematic review and meta-analysis of clinical outcomes of early caffeine therapy in preterm neonates. Br J Clin Pharmacol. 2017;83(1):180-191.
6. Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, et al. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr. 2015;169(1):33-38.
7. Patel RM, Leong T, Carlton DP, Vyas-Read S. Early caffeine therapy and clinical outcomes in extremely preterm infants. J Perinatol. 2013;33(2):134-140.
8. Park HW, Lim G, Chung SH, Chung S, Kim KS, Kim SN. Early Caffeine Use in Very Low Birth Weight Infants and Neonatal Outcomes: A Systematic Review and Meta-Analysis. J Korean Med Sci. 2015;30(12):1828-1835.
9. Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med. 2014;33(7):1242-1258.
10. Amaro CM, Bello JA, Jain D, Ramnath A, D'Ugard C, Vanbuskirk S, et al. Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial. J Pediatr. 2018;196:52-57.
Early Caffeine and Neurodevelopmental Outcomes
We read with interest the recent article by Lodha et al.1, entitled “Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants”. The authors found a significant association between caffeine administered before and after 2 days in a logistic regression analysis for short term outcomes (bronchopulmonary dysplasia (BPD) and patent ductus arteriosis (PDA)) as well as neurodevelopmental outcomes. They also reported a post hoc propensity score matched analysis demonstrating significantly less cerebral palsy (CP) and hearing impairment in the early caffeine group.
We suggest these statements and results be approached with caution. Although this study and most similar ones have shown an advantage of early caffeine, they have all been retrospective and observational1-3. Infants in the early caffeine group were significantly more mature, higher birthweight, less ill and less growth restricted (SGA) than the late caffeine group. The authors attempt to adjust for these confounders using propensity scoring for 445 matched pairs, eliminating 71% of the early caffeine group and 21% of the late caffeine group from analysis. This analysis assumes that there are no unobserved variables between groups and ignores birthweight as a confounder. We believe there may be other unobserved variables present when a neonatologist is evaluating an infant and deciding if caffeine treatment is clinically appropriate.
The CAP randomized controlled trial clearly showed a benefit of caffeine versus no caffeine for outcomes but did not address early or late dosing, as caffeine administration was started between 3 and 10 days4. In the absence of a prospective, randomized trial of early versus late caffeine it is premature to suggest that caffeine administration be considered “a priority once the neonate is stabilized”. A recent randomized controlled trial was stopped early due to a trend of a higher mortality in the early caffeine group5. As we have seen many times in our field “irrational exuberance” for a therapy may lead to untoward consequences. In our opinion, it remains too early to recommend early caffeine.
References
1. Lodha A, Entz R, Synnes A, et al. Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants. Pediatrics 2019;143.
2. Dobson NR, Patel RM, Smith PB, et al. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. The Journal of Pediatrics 2014;164:992-8 e3.
3. Hand I, Zaghloul N, Barash L, Parris R, Aden U, Li HL. Timing of Caffeine Therapy and Neonatal Outcomes in Preterm Infants: A Retrospective Study. International Journal of Pediatrics 2016;2016:9478204.
4. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. The New England Journal of Medicine 2006;354:2112-21.
5. Amaro CM, Bello JA, Jain D, et al. Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial. The Journal of Pediatrics 2018;196:52-7.